High-performance Dual Combination Therapy For Cancer Treatment With Hybrid Membrane-camouflaged Mesoporous Silica Gold Nanorods

BackgroundThe traditional chemotherapy and radiotherapy are usually unable to distinguish tumor cells and normal cells and cause significant side effects.With the development of nanotechnology,scientists aim to design high anti-tumor nano-medicine.However,the development of nano-medicine encounter some difficulties such as how to increase the loading efficiency?How to avoid off-target effect?And how to develop nanomedicines with multiple functions for combination therapy?In light of these considerations,our project developed a multi-functional gold nanorod nanoplatform with hybrid membrane camouflaged,which can achieve the functions of homo-targeting,non-invasive tracking,chemotherapy and photothermal therapy,aiming to provide new ideas and methods for tumor therapy.ObjectiveThe research aim to design a new cancer therapy platform,red blood cell membrane and tumor cell membrane were used to form the hybrid membrane to modified DOX-loaded and silica-coated gold nanorods.Hybrid membrane preserved specific protein of the cell membrane,which makes the nanoparticles has the property of red blood cells and cancer cells.This nano-platform had the abilities of escaping the capture of the immune cells in the body,prolonging the cycle time of drug in the body,increasing the ability of targeting tumor cells.It also improved the drug loading efficiency.More over,the photoacoustic response of gold nanorods makes it possible to monitor the tumor treatment process by imaging technology in real time.The combination of photothermal therapy and chemotherapy can enhance the efficiency of tumor treatment,shorten the duration of treatment and minimize the side effects of chemotherapy drugs.Methods1.The morphology and structure were characterized by DLS,TEM,UV spectrophotometry,fluorescence spectrophotometry and nitrogen adsorption.2.The fusion of HRMSGD surface membrane protein components with the membrane was analyzed by SDS-PAGE,Western-blot and CLSM.3.The photothermal conversion of gold nanorods were detected by 808nm near-infrared laser.4.CLSM,FAC,TEM and nuclear dye(Hoechst 33342)were used to analyzed the uptake of HEMSGD by He La cells.Lysosome tracker was used to study the ability of escaping lysosomal capture.5.The multimode imaging function of HRMSGD was performed by photothermal imaging,photoacoustic imaging and fluorescence imaging.6.The anti-tumor effect of HRMSGD in vitro was studied by CCK-8 and live dead assay.A mouse cervical carcinoma xenograft model was established to analyze the distribution and antitumor activity of HRMSGD in vivo.7.RNA-seq was performed to study the anti-tumor mechanism of HRMSGD.Results1.DLS results showed that the size of HRMSG is about 148.9nm;The results of TEM revealed that the nanoparticles morphology was elliptic and the distribution was uniform without aggregation.The UV results showed that there are strong absorption peaks at 850nm and 500nm.Fluorescence spectrophotometry results showed that the absorption peak of HRMSGD was obvious at 490nm.Nitrogen adsorption analysis illustrated that the MSG had a qualified mesoporous structure.2.SDS-PAGE and Weatern-blot results indicated that HRMSGD retain the most of the protein of the original cell membrane,and the mixed fluorescence of the two membrane formed yellow fluorescence under CLSM.3.The photothermal stability of HRMSGD remained unchanged after 5 cycles.The temperature varied with the radiation time and power and reached to 65℃after 6min radiation with 2W/cm~2.4.The intake results of HRMSGD was time-dependent and concentration-dependent.The cell intake reached saturation after incubated with HRMSGD 5μM for 8h.More over,a series of modification of gold nanoparticles had no effect on the release of DOX,which was similar to the absorption of DOX molecular.5.In vivo distribution analysis showed that HRMSGD could accurately target the tumor tissue and accumulated in the tumor site for a long time.6.CCK8 results showed that the tumor cell inhibition effect of HRMSGD-L group is the best,it could inhibit 85%Hela cells grouth.The results of live dead assay showed obvious PI red fluorescence in HRMSGD group after 3 minutes of laser irradiation.The tumors of the HRMSGD-L group were significantly suppressed,showing good anti-tumor effect and basically non-toxic side effect.H&E staining results indicated that no significant physiological morphological changes were observed in the main organs of mice treated with HRMSGD-L.Tunnel staining results showed that most of the cells in the HRMSGD-L group showed red fluorescence,indicating that they were dead tumor cells.7.RNA-seq results showed that the apoptosis induced by HRMSGD was related to a variety of genes regulation.ConclusionThe biomimetic engineering gold nanorod carriers can achieve the targeted delivery and release of DOX precisely,enhance the therapeutic effect of chemotherapy and reduce the toxicity.At the same time,it can further reduces the side effects of chemotherapy and shortens the therapy time.The entire delivery system integrates photothermal therapy,chemotherapy,and multimodal imaging functions.Provide new ideas for clinical research on the integration of tumor diagnosis and treatment.